Poole Candace J, Zheng Wenli, Lee Haesung, Young Danielle, Lodh Atul, Chadli Ahmed, van Riggelen Jan
Department of Biochemistry and Molecular Biology, Augusta University, 1410 Laney-Walker Blvd., Augusta, GA 30912, USA.
Georgia Cancer Center, Augusta University, 1410 Laney-Walker Blvd., Augusta, GA 30912, USA.
Cancers (Basel). 2018 Nov 16;10(11):448. doi: 10.3390/cancers10110448.
Overexpression of the MYC oncogene is a key feature of many human malignancies including Burkitt lymphoma. While MYC is widely regarded to be a promising therapeutic target, a clinically effective MYC inhibitor is still elusive. Here, we report an alternative strategy, targeting MYC indirectly through inhibition of the HSP90 machinery. We found that inhibition of HSP90 function reduces MYC expression in human Burkitt lymphoma through suppression of MYC transcription and destabilization of MYC protein, thereby diminishing the proliferation of tumor cells. Consistently, treatment of Burkitt lymphoma cell lines with HSP90 inhibitors (17-AAG or 17-DMAG) was accompanied by downregulation of canonical MYC target genes. Combination treatment with 17-DMAG and the proteasome inhibitor, MG-132, led to accumulation of MYC protein, indicating that upon HSP90 inhibition, MYC is degraded by the proteasome. Using co-immunoprecipitation, we furthermore demonstrated a direct interaction between MYC and HSP90, indicating that MYC is an HSP90 client protein in Burkitt lymphoma. Together, we report here the use of HSP90 inhibitors as an alternative approach to target the MYC oncogene and its network in Burkitt lymphoma.
MYC癌基因的过表达是包括伯基特淋巴瘤在内的许多人类恶性肿瘤的一个关键特征。虽然MYC被广泛认为是一个有前景的治疗靶点，但临床上有效的MYC抑制剂仍然难以捉摸。在此，我们报告一种替代策略，即通过抑制HSP90机制间接靶向MYC。我们发现抑制HSP90功能可通过抑制MYC转录和使MYC蛋白不稳定来降低人类伯基特淋巴瘤中MYC的表达，从而减少肿瘤细胞的增殖。一致地，用HSP90抑制剂（17-AAG或17-DMAG）处理伯基特淋巴瘤细胞系伴随着经典MYC靶基因的下调。17-DMAG与蛋白酶体抑制剂MG-132联合处理导致MYC蛋白积累，表明在HSP90抑制后，MYC被蛋白酶体降解。通过免疫共沉淀，我们进一步证明了MYC与HSP90之间的直接相互作用，表明MYC是伯基特淋巴瘤中的一种HSP90客户蛋白。总之，我们在此报告使用HSP90抑制剂作为在伯基特淋巴瘤中靶向MYC癌基因及其网络的一种替代方法。
